PROJECT SUMMARY We propose to investigate how the chemokine CXCL12 (SDF-1?), and its main receptor, CXCR4, are influenced by exposure to the synthetic cathinone MDPV (methylenedioxypyrovalerone), and, in turn, how CXCL12/CXCR4 antagonism influences behavioral and neurochemical correlates of synthetic cathinone (ab)use. Different cathinones are found in bath salts products, but MDPV and its next-generation analogs appear more apt to cause life-threatening medical consequences including hypertension, tachycardia, aggression and suicide. Part of the problem with MDPV, as well as more traditional illicit psychostimulants such as cocaine, is a highly-addictive phenotype that perpetuates ongoing drug taking and relapse to drug taking. MDPV, similar to cocaine, blocks cellular monoamine reuptake but with enhanced potency at DAT and NET. Little is known about how non-monoamine systems in the brain reward pathway are affected by MDPV and contribute to its addictive effects. Since there is still no approved medication available for cocaine abuse, let alone for synthetic cathinones, it is anticipated that a new target, a new approach or both will lead to the first approved pharmacotherapy. Our proposed target is a chemokine, specifically CXCL12, and its receptor CXCR4. CXL12 is one of the few chemokines found in the brain. It also has a FDA-approved, commercially- available antagonist (AMD3100) to investigate a CXCR4-receptor mechanism. Notably, of all the chemokines, CXCL12 is the one most linked to psychostimulant addiction. Mice exposed to acute cocaine display increased plasma levels of CXCL12. In human cocaine abusers, CXCL12 is the only chemokine correlated to the history of pathological cocaine use and severity of dependence. Recently, we took the critical next step of linking the CXCL12/CXCR4 system in the mesolimbic dopamine circuit with psychostimulant reward by showing that repeated cocaine exposure increases CXLC12 gene expression in the midbrain ventral tegmental area (VTA) and produces place preference in rats that is reduced by a CXCR4 antagonist (AMD3100). The efficacy of CXCR4 antagonism extends to MDPV-induced behaviors, as our data show that AMD3100 reduces MDPV place preference, locomotor activation, and acquisition (self-administration) in rats. We propose behavioral, cellular and neurochemical experiments to test the hypotheses that CXCL12 and CXCR4 in the mesolimbic DA circuit are dysregulated by MDPV exposure and abstinence and that genetic or pharmacological antagonism of CXCR4 receptors in the VTA reduces MDPV acquisition, reinforcement and relapse by decreasing mesolimbic dopamine (DA) output. By providing information about how interplay between chemokine and mesolimbic brain reward systems impact psychostimulant addiction, we expect to identify CXCL12/CXCR4 as a chemokine- based therapeutic target for countering adverse effects of both new and established psychostimulant drugs.